Glyceride‐Mimetic Prodrugs Incorporating Self‐Immolative Spacers Promote Lymphatic Transport,Avoid First‐Pass Metabolism,and Enhance Oral Bioavailability

First‐pass hepatic metabolism can significantly limit oral drug bioavailability. Drug transport from the intestine through the lymphatic system, rather than the portal vein, circumvents first‐pass metabolism. However, the majority of drugs do not have the requisite physicochemical properties to facilitate lymphatic access. Herein, we describe a prodrug strategy that promotes selective transport through the intestinal lymph vessels and subsequent release of drug in the systemic circulation, thereby enhancing oral bioavailability. Using testosterone (TST) as a model high first‐pass drug, glyceride‐mimetic prodrugs incorporating self‐immolative (SI) spacers, resulted in remarkable increases (up to 90‐fold) in TST plasma exposure when compared to the current commercial product testosterone undecanoate (TU). This approach opens new opportunities for the effective development of drugs where oral delivery is limited by first‐pass metabolism and provides a new avenue to enhance drug targeting to intestinal lymphoid tissue.     

Studies on oral bioavailability and first‐pass metabolism of withaferin A in rats using LC–MS/MS and Q‐TRAP

Withaferin A (WA) is one of the major bioactive steroidal lactones with extensive pharmacological activities present in the plant Withania somnifera. The absolute oral bioavailability of WA remains unknown and human‐related in vitro data are not available. Therefore, in the present study, the absolute oral bioavailability of WA in male rats and the in vitro screening of absorption factors by Q‐trap and LC–MS/MS analysis were conducted to explore possible clinical properties of WA. The developed and validated analytical methods were successfully applied to the pharmacokinetic studies and in vitro measurement of WA. The oral bioavailability was determined to be 32.4 ± 4.8% based on intravenous (5 mg/kg) and oral (10 mg/kg) administrations of WA in male rats. The in vitro results showed that WA could be easily transported across Caco‐2 cells and WA did not show as a substrate for P‐glycoprotein. Moreover, the stability of WA was similar between male rat and human in simulated gastric fluid (stable), in intestinal microflora solution (slow decrease) and in liver microsomes (rapid depletion, with a half‐life of 5.6 min). As such, the first‐pass metabolism of WA was further verified by rat intestine‐liver in situ perfusion, revealing that WA rapidly decreased and 27.1% remained within 1 h, while the content of three major metabolites (M1, M4, M5) identified by Q‐trap increased. This perfusion result is consistent with the oral bioavailability results in vivo. The first‐pass metabolism of WA might be the main barrier in achieving good oral bioavailability in male rats and it is predicted to be similar in humans. This study may hold clinical significance.     

Hepatic,gastric and intestinal first‐pass effects of vitexin‐2′′‐O‐rhamnoside in rats by ultra‐high‐performance liquid chromatography

Previous research in our laboratory found that the absolute bioavailability of vitexin‐2′′‐O‐rhamnoside (VR) was quite low at 4.89%. A rapid and sensitive UHPLC method using hesperidin as an internal standard was therefore developed and validated to investigate the reasons for this by determining VR in rat plasma after administering intravenously, intraportally (5 mg/kg), intraduodenally and intragastrically (40 mg/kg) to the rat model of the hepatic, gastric and intestinal first‐pass effects. As only a high intestinal first‐pass effect of VR was found, that is, there existed a low bioavailability of VR (2.40%), inhibitors of P‐glycoprotein (P‐gp) and cytochrome P450 3A (CYP3A), including verapamil, cyclosporin A and midazolam, and absorption enhancers, including bile salts and borneol, combined with VR, were instilled into duodenum to evaluate the effects on bioavailability of VR. The results demonstrated that area under the concentration–time curve (AUC) values of VR slightly increased after administration of verapamil, cyclosporin A and midazolam, indicating that CYP3A and P‐gp do not play an important role in the first‐pass effect in the intestine. AUC values of VR significantly increased after administering bile salts or borneol, indicating that the low bioavailability of VR was mainly related to its poor absorption in the intestine. Copyright © 2015 John Wiley & Sons, Ltd.     

Strawberry Decreases Intraluminal and Intestinal Wall Hydrolysis of Testosterone Undecanoate

Male hypogonadism is often treated by testosterone (T) replacement therapy such as oral administration of the ester prodrug, testosterone undecanoate (TU). However, the systemic exposure to T following oral TU is very low due to esterase-mediated metabolism, particularly in the small intestine. The aim of this work was to examine the esterase-inhibitory effect of natural fruit extract of strawberry (STW) on the intestinal degradation of TU as a potential approach to increasing the oral bioavailability of T. Herein, the hydrolysis of TU was assessed in fasted state simulated intestinal fluid with added esterase activity (FaSSIF/ES) and Caco-2 cell homogenates in the presence of STW extract. It is noteworthy that STW substantially inhibited the degradation of TU in FaSSIF/ES and Caco-2 cell homogenates at concentrations that could be achieved following oral consumption of less than one serving of STW fruit. This can significantly increase the fraction of unhydrolyzed TU in the intestinal lumen as well as in enterocytes. In addition, it was demonstrated that TU has high intestinal lymphatic transport potential as the association of TU with plasma-derived human chylomicrons was in the range of 84%. Therefore, oral co-administration of TU with STW could potentially increase the intestinal stability of TU and consequently the contribution of lymphatically delivered TU to the systemic exposure of T in vivo.     

Increased Affinity of 2′‐O‐(2‐Methoxyethyl)‐Modified Oligonucleotides to RNA through Conjugation of Spermine at Cytidines

Structural modification at the 2′‐O‐position of riboses in oligonucleotide therapeutics is of critical importance for their use as drugs. To date, the methoxyethyl (MOE) substituent is the most important and features in dozens of antisense oligonucleotides that have been tested in clinical trials. Yet, the search for new improved modifications continues in a quest for increased oligonucleotide potency, improved transport in vivo and favorable metabolism. Recently, we described how the conjugation of spermine groups to pyrimidines in oligonucleotides vastly increases their affinity for complementary RNAs through accelerated binding kinetics. Here we describe how spermines can be linked to the exocyclic amino groups of cytidines in MOE‐oligonucleotides employing a straightforward ‘convertible nucleoside approach’ during solid phase synthesis. Singly‐ or doubly‐modified oligonucleotides show greatly enhanced affinity for complementary RNA, with potential for a new generation of MOE‐based oligonucleotide drugs.     

Film‐ and ointment‐based delivery systems for the transdermal delivery of TNP‐470

Pathological angiogenesis, the process of new blood vessel formation, is responsible for a broad range of neovascular‐related systemic diseases. One of the first antiangiogenic compounds tested in clinical trials against cancer was TNP‐470. Despite promising activity the injectable drug showed poor plasma stability and caused adverse side effects in high doses lead to termination of the trials. In our current work, we introduce the development of a transdermal delivery systems for controlled release of TNP‐470. Such formulation can potentially reduce toxicity due to controlled continuous dosing and improve stability by avoiding gastrointestinal first pass metabolism. Although transdermal delivery is a very challenging route for drug administration due to the low permeability of the skin, here we present a successful development of two different drug delivery systems, film and ointment for dermal application of TNP‐470. Chitosan film had high loading capacity of up to 50% w/w of TNP‐470 compared with 10% maximum loading in hydrocarbon ointment. A detailed step‐by‐step development of TNP‐470 films, from the initial solvent screening to final optimized formulation, is presented. Ex vivo skin permeation studies demonstrated a superior release of the drug from the film formulation compared with the ointment. Furthermore, histological test of the skin confirmed ointment safety showing no evidence of skin tissues damage. Our results present novel, promising, controlled release drug delivery systems with improved stability, efficacy, and safety profile of TNP‐470 via transdermal route.     

Solid dispersion systems engineered from hydroxypropyl‐β‐cyclodextrin and water‐soluble polymers for enhanced oral bioavailability of nimodipine

Nimodipine (NMD) is a calcium channel blocker that is used in the treatment of cerebrovascular disorders, such as stroke indicated for biological rhythm and neurological disorders. According to biopharmaceutical classification, NMD is categorized as a class ΙΙ drug, meaning it has a poor solubility profile. The objective of this experiment is to prepare multicomponent systems to enhance the solubility, dissolution, and bioavailability of NMD. Inclusion complex and solvent evaporation techniques have been exploited to overcome this challenge. in vitro dissolution studies and solubility, the profile was performed in three pH media (pH 7.5, 1.2, and 6.8). The drug release at (Q_60min) for SD‐PVP3 was 33‐fold higher than pure NMD in double‐distilled water. The solubility of SD PVP3 was about 30 times higher than plain NMD in double‐distilled water. A pharmacokinetic study in rats indicated that the AUC_0‐720 value of the inclusion complex (NMD‐KD) was 1.63‐fold higher than pure NMD. At the same time, the solid dispersion (NMD‐SD PVP3) was 3.94‐fold higher than that of plain NMD, indicating a significant increase in the bioavailability of NMD. The combination of the inclusion complex and solvent evaporation method led to the formation of new solid dispersions (SD PLX and SD PVP), which significantly increased the solubility, dissolution, and the oral bioavailability of NMD.     

The application of biomacromolecules to improve oral absorption by enhanced intestinal permeability: A mini-review

Oral administration has been widely regarded as the most convenient, quick and safe approach compared to other routes of drug delivery. However, oral absorption of drugs is often limited due to rigorous environments and complex obstacles in gastrointestinal tract. Having received considerable attention, biomacromolecules have been applied for oral drug delivery to improve the bioavailability, which could be attributed to its stability and unique bioactivities, including intestinal adhesion, opening of epithelial tight junctions, inhibiting cell efflux and regulating relative protein expression. Specifically, enhancing intestinal permeability has been regarded as a promising strategy for improving bioavailability of oral drug delivery. In this review, a series of biomacromolecules and the related mechanisms of increasing intestinal permeability for enhanced oral bioavailability are comprehensively classified and elucidated. In addition, recent advances in biomacromolecules based oral delivery and related future directions are mentioned and predicted in this review article.     

Pharmacokinetics and metabolism of olerciamide A from Portulaca oleracea L. in rats by UHPLC‐UV and UHPLC‐ESI‐Q‐TOF/MS

The aim of this study was to elucidate the pharmacokinetics of olerciamide A in rats after oral and intravenous administration of Portulaca oleracea L. extract by a simple and rapid ultra high‐performance liquid chromatography method with bergapten as internal standard. The pharmacokinetic results indicated that olerciamide A was rapidly distributed with a time to peak concentration of 30 min after oral administration and presented a low oral absolute bioavailability of 4.57%. The metabolism of olerciamide A in rats was also investigated using ultra‐high‐performance liquid chromatography electrospray coupled with quadrupole–time of flight mass spectrometry to elucidate the reason for the low absolute bioavailability of olerciamide A and seven metabolites of oleraciamide A were found in rat plasma and urine.     

A rapid and sensitive LC‐MS/MS method for evaluation of the absolute oral bioavailability of a novel c‐Met tyrosine kinase inhibitor QBH‐196 in rats

A sensitive, selective and high‐throughput UPLC‐MS/MS method was developed and validated for the determination of a novel c‐Met tyrosine kinase inhibitor, QBH‐196, in rat plasma. QBH‐196 and its analog BH357 (IS) were extracted from rat plasma using a mixture of dichloromethane and N‐hexane (2:3, v/v). The chromatographic separation was carried out on Phenomenex C₁₈ column (50 × 2.1 mm, 2.6 µm particle size) with a gradient mobile phase of methanol (A) and water containing 0.05% formic acid (B) at a flow rate of 0.2 mL/min. The assay was performed by positive electrospray ionization in multiple reaction monitoring mode using transitions of m/z 622.68 → 140.41 for QBH‐196 and m/z 591.19 →126.21 for the IS, respectively. Good linearity was obtained over the concentration range of 8.0–4000 ng/mL (r² > 0.99) for QBH‐196 and the lower limit of quantification was 8.0 ng/mL in rat plasma. Validations of the method, including its sensitivity, extraction recovery, matrix effect, intra‐ and inter‐day precision, accuracy and stability, were all within acceptable limits. The established method was successfully applied to determine absolute oral bioavailability of QBH‐196 in rats for the first time. The mean oral absolute bioavailability of QBH‐196 was found to be about 40.8% and the elimination half‐life was 40.0 ± 13.1 h. This result suggested that QBH‐196 exhibits good oral absorption in vivo, which is very important for the further development of QBH‐196 as a new oral anticancer drug. Copyright © 2015 John Wiley & Sons, Ltd.     

Synthesis,Antioxidant, and Anti‐Inflammatory Evaluation of Novel Thiophene‐Fused Quinoline Based β‐Diketones and Derivatives

Novel thieno[2,3‐b ]quinoline‐2‐carboxylic acid derivatives including β‐diketone, pyrazole, and flavone were prepared under ultrasonication and evaluated for in vitro antioxidant and anti‐inflammatory activities. Antioxidant activity was determined by DPPH radical scavenging method and anti‐inflammatory activity by HRBC membrane stabilization method. Some of the Compounds showed good antioxidant activity, whereas, some of the compounds bearing pyrazole core showed good anti‐inflammatory activity. Further in silico physicochemical properties were also calculated for good oral drug bioavailability and drug likeness of synthesized compounds.     

Hydrogen‐Bonded Films for Zero‐Order Release of Leuprolide

Leuprolide has been widely used in androgen deprivation therapy for the treatment of advanced prostate cancer, but its use is still limited due to its short half‐life. Herein, hydrogen‐bonded layer‐by‐layer films are fabricated from PEGylated leuprolide (PEG‐LEU) and tannic acid (TA). Because of its dynamic nature, the film disintegrates gradually in water and releases PEG‐LEU and TA. The in vitro release profile indicated perfect zero‐order kinetics, which is explained by the unique release mechanism. When implanted subcutaneously in male rats, the films maintain a constant serum drug level. For a 60‐bilayer film, the serum drug level is maintained constant for ≈24 days. No initial burst release is observed, suggesting that the in vivo release also follows zero‐order kinetics. Initially, an increase in the level of serum testosterone is induced by the released drug, followed by testosterone suppression to a constant level below the castrate level, which could be maintained as long as a constant serum drug level is maintained. Since the new drug carriers avoid an initial burst release of the drug and maintain a constant serum drug level and hence a constant serum testosterone level below the castrate level, these carriers are highly promising for androgen deprivation therapy.     

Metabolism of cyadox by the intestinal mucosa microsomes and gut flora of swine,and identification of metabolites by high‐performance liquid chromatography combined with ion trap/time‐of‐flight mass spectrometry

Cyadox (CYX), 2‐formylquinoxaline‐1,4‐dioxide cyanoacetylhydrazone, is an antimicrobial and growth‐promoting feed additive for food‐producing animals. To reveal biotransformation of CYX in swine intestine, CYX was incubated with swine intestinal microsomes and mucosa in the presence of an NADPH‐generating system and swine ileal flora and colonic flora, respectively. The metabolites of CYX were identified using high‐performance liquid chromatography combined with ion trap/time‐of‐flight mass spectrometry (LC/MS‐ITTOF). Structural elucidation of the metabolites was precisely performed by comparing their changes in molecular mass, full scan MS/MS spectra and accurate mass measurements with those of the parent drug. Finally, seven metabolites were identified as follows: three reduced metabolites (cyadox 1‐monoxide (Cy1), cyadox 4‐monoxide (Cy2) and bisdesoxycyadox (Cy4)); hydroxylation metabolite (3‐hydroxylcyadox 1‐monoxide (Cy3)); hydrolysis metabolite of the amide bond (N‐decyanoacetyl cyadox (Cy5)); a hydrogenation metabolite (11,12‐dihydro‐bisdesoxycyadox (Cy6)) and a side‐chain cleavage metabolite (2‐hydromethylquinoxaline (Cy7)). Only one metabolite (Cy1) was found in intestinal microsomes. Cy1, Cy2 and Cy4 were detected in intestinal mucosa, ileal and colonic flora. In addition, Cy3 and Cy5 were only obtained from ileal flora, and Cy6 and Cy7 alone were observed in colonic bacteria. The results indicated that N → O group reduction was the main metabolic pathway of CYX metabolism in swine ileal flora, intestinal microsomes and mucosa. New metabolic profiles of hydrogenation and cleavage on the side chain were found in colonic bacteria. Among the identified metabolites, two new metabolites (Cy6, Cy7) were detected for the first time. These studies will contribute to clarify comprehensively the metabolism of CYX in animals, and provide evidence to explain the pharmacology and toxicology effects of CYX in animals. Copyright © 2011 John Wiley & Sons, Ltd.     

Enhancement of bioavailability of dopamine via nasal route in beagle dogs.

Dopamine (DA), which is ineffective by oral administration due to first pass metabolism and is usually injected, was administered to dogs via rectal, dermal, buccal and nasal routes. The nasal route had the highest bioavailability and best avoided first pass metabolism. The effects of the addition of hydroxypropyl cellulose (HPC), sodium deoxycholate, POE (6) hydrogenated caster oil (HCO-60) and Azone on the nasal absorption increased bioavailability from 11.7% (control) to about 20%, 35%, 25% and 68%, respectively. Further, with a combination of 2% HPC and 5% Azone, bioavailability was increased to almost the same level as with i.v. administration. At the same time, plasma concentrations were maintained at a high level for more than 7 h. The increase in bioavailability is presumed to be caused by an enhancement in absorption and prolongation of the time DA is retained in the nasal cavity due to Azone and HPC, respectively.     

Improved Safety and Anti-Glioblastoma Efficacy of CAT3-Encapsulated SMEDDS through Metabolism Modification

13a-(S)-3-pivaloyloxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (CAT3) is a novel oral anti-glioma pro-drug with a potent anti-tumor effect against temozolomide-resistant glioma. 13a(S)-3-hydroxyl-6,7-dimethoxyphenanthro(9,10-b)-indolizidine (PF403) is the active in vivo lipase degradation metabolite of CAT3. Both CAT3 and PF403 can penetrate the blood–brain barrier to cause an anti-glioma effect. However, PF403, which is produced in the gastrointestinal tract and plasma, causes significant gastrointestinal side effects, limiting the clinical application of CAT3. The objective of this paper was to propose a metabolism modification for CAT3 using a self-microemulsifying drug delivery system (SMEDDS), in order to reduce the generation of PF403 in the gastrointestinal tract and plasma, as well as increase the bioavailability of CAT3 in vivo and the amount of anti-tumor substances in the brain. Thus, a CAT3-loaded self-microemulsifying drug delivery system (CAT3-SMEDDS) was prepared, and its physicochemical characterization was systematically carried out. Next, the pharmacokinetic parameters of CAT3 and its metabolite in the rats’ plasma and brain were measured. Furthermore, the in vivo anti-glioma effects and safety of CAT3-SMEDDS were evaluated. Finally, Caco-2 cell uptake, MDCK monolayer cellular transfer, and the intestinal lymphatic transport mechanisms of SMEDDS were investigated in vitro and in vivo. Results show that CAT3-SMEDDS was able to form nanoemulsion droplets in artificial gastrointestinal fluid within 1 min, displaying an ideal particle size (15–30 nm), positive charge (5–9 mV), and controlled release behavior. CAT3-SMEDDS increased the membrane permeability of CAT3 by 3.9-fold and promoted intestinal lymphatic transport. Hence, the bioavailability of CAT3 was increased 79% and the level of its metabolite, PF403, was decreased to 49%. Moreover, the concentrations of CAT3 and PF403 were increased 2–6-fold and 1.3–7.2-fold, respectively, in the brain. Therefore, the anti-glioma effect in the orthotopic models was improved with CAT3-SMEDDS compared with CAT3 in 21 days. Additionally, CAT3-SMEDDS reduced the gastrointestinal side effects of CAT3, such as severe diarrhea, necrosis, and edema, and observed less inflammatory cell infiltration in the gastrointestinal tract, compared with the bare CAT3. Our work reveals that, through the metabolism modification effect, SMEDDS can improve the bioavailability of CAT3 and reduce the generation of PF403 in the gastrointestinal tract and plasma. Therefore, it has the potential to increase the anti-glioma effect and reduce the gastrointestinal side effects of CAT3 simultaneously.     

A Twist‐Assisted Biphenyl Photosensitizer Passable Through Glucose Channel

While the development of low‐molecular‐weight drugs is saturating, agents for photodynamic therapies (PDTs) may become alternative seeds in pharmaceutical industry. Among them, orally administrative, cancer‐selective, and side effect‐free photosensitizers (PSs) that can be activated by tissue‐penetrative near‐infrared (NIR) lights are strongly demanded. We discovered such a PS from scratch by focusing on a twist‐assisted spin‐orbit charge transfer intersystem crossing (ISC) mechanism in a biphenyl derivative, which was demonstrated by thorough photophysical studies. The unique ISC mechanism enables the PS to be small and slim so as to pass through glucose transporters and exert a PDT effect selectively on a cancer cell line. The smallness will allow for oral administration and fast clearance, which have been agenda of approved PSs with larger molecular weights. We also demonstrated that our PS was able to be activated with an NIR pulse laser through two‐photon excitation.     

Lipid-Based Nanocarrier System for the Effective Delivery of Nutraceuticals

Nutraceuticals possess several health benefits and functions; however, most nutraceuticals are prone to degradation in the gastrointestinal environment and have poor bioavailability. Application of a novel carrier system is of increasing importance to overcome obstacles and provide efficient applicability. Lipid-based nanocarriers provide a large surface-to-mass ratio, enhanced intestinal absorption by solubilization in the intestinal milieu, intestinal lymphatic transport, and altering enterocyte-based transport. A critical overview of the current limitation, preparation, and application of lipid-based nanocarriers (liposomes and niosomes) and lipid nanoparticles (SLNs and NLCs) is discussed. Physical and gastrointestinal stability and bioavailability of nanoencapsulated nutraceuticals are considered as well.     

Bioanalytical method validation,biopharmaceutical and pharmacokinetic evaluation of GSK-650394, a serum- and glucocorticoid-regulated kinase 1 inhibitor

GSK-650394 is an inhibitor of serum- and glucocorticoid-regulated kinase 1 that displays potency for treating cancer, hypertension, cardiovascular and neuronal diseases, such as Parkinson’s disease. However, the biopharmaceutical properties and pharmacokinetics of GSK-650394 have not been studied extensively. Also, there are currently no bioanalytical assays available for this new drug candidate. In this study, we developed a simple and sensitive liquid chromatography-tandem mass spectrometry method to quantify GSK-650394 in rat plasma and validated its selectivity, linearity, accuracy and precision, sensitivity, matrix effects, extraction recovery, and stability, following the United States Food and Drug Administration guidelines. In vitro studies showed the biopharmaceutical properties of GSK-650394, including its low solubility in water and simulated gastrointestinal fluids, passive transport in Caco-2 cell monolayers, high plasma protein binding, and primary metabolism by glucuronide conjugation in the small intestine and liver of rats. Following intravenous administration (2 mg/kg) to rats, GSK-650394 exhibited low total clearance (11.18 ± 1.28 mL/min/kg) and volume of distribution at steady-state (346.1 ± 120.6 mL/kg). Following oral administration (2, 5, and 10 mg/kg) to rats, GSK-650394 underwent enterohepatic circulation, with low bioavailability (～9%). The insignificant difference in bioavailability among three oral doses suggests that GSK-650394 may follow linear pharmacokinetics up to an oral dose of 10 mg/kg. In addition, the total form of parent drug and glucuronide conjugate in rat plasma from three oral doses showed a much higher value of area under the plasma concentration versus time curve than the parent drug, indicating that the primary metabolism process of GSK-650394 was glucuronidation. Our findings suggest that the low oral bioavailability of GSK-650394 is associated with its low solubility, instability under acidic gastric conditions, and extensive glucuronidation metabolism.     

Multi‐analysis strategy for metabolism of Andrographis paniculata in rat using liquid chromatography/quadrupole time‐of‐flight mass spectrometry

Compared with chemical drugs, it is a huge challenge to identify active ingredients of multicomponent traditional Chinese medicine (TCM). For most TCMs, metabolism investigation of absorbed constituents is a feasible way to clarify the active material basis. Although Andrographis paniculata (AP) has been extensively researched by domestic and foreign scholars, its metabolism has seldom been fully addressed to date. In this paper, high‐performance liquid chromatography/quadrupole time‐of‐flight mass spectrometry was applied to analysis and characterization of AP metabolism in rat urine and feces samples after oral administration of ethanol extract. The differences in metabolites and metabolic pathways between the two biological samples were further compared. The chemical structures of 20 components were tentatively identified from drug‐treated biological samples, including six prototype components and 14 metabolites, which underwent such main metabolic pathways as hydrolyzation, hydrogenation, dehydroxylation, deoxygenation, methylation, glucuronidation, sulfonation and sulfation. Two co‐existing components were found in urine and feces samples, suggesting that some ingredients' metabolic processes were not unique. This study provides a comprehensive report on the metabolism of AP in rats, which will be helpful for understanding its mechanism. Copyright © 2014 John Wiley & Sons, Ltd.     

A Porous Zn2(abct) Framework as an Efficient Carrier for 5‐Fu Delivery and Inhibiting Human Liver Cancer Cells

The creation of effective drug delivery systems is very important in diagnosis and treatment of cancer through controlled and targeted drug delivery. They can increase bioavailability of drugs and reduce their side effects. Metal‐organic frameworks (MOFs) are alternative drug delivery systems, which are suitable for targeted drug delivery due to their adjustable pore sizes and compatibility by adding some functional groups. In this work, a new porous Zn^II‐organic framework was fabricated using a tetracarboxylic acid linker 3,3′,5,5′‐azobenzene‐tetracarboxylic acid (H₄abct), which reveals a 3D channel‐type framework with a high free pore volume. The performance of the solvent‐free samples was studied on absorbing and releasing 5‐fluorouracil (5‐Fu). Characterization methods, such as FT‐IR, PXRD, HPLC, BET measurement, and GCMC simulations, were employed to characterize the 5‐Fu loaded framework. Furthermore, anticancer properties of the MOF and drug‐loaded MOF were investigated against four human liver cancer cells (HepG2, SMMC‐7721, HuH‐7 and MHCC‐97H).